1. Field of the Invention
The present invention relates to stilbenoids that exhibit hypoglycemic and/or antidiabetic activity in mammals. Provided herein are processes for obtaining such stilbenoids, particularly from Cajanus cajun; compositions comprising the stilbenoids and methods for their use in treating diabetes mellitus and lowering blood glucose.
2. Related Art
Uses of Cajanus SPP
Plants of Cajanus spp. (Leguminoseae), particularly C. cajun, also known as pigon pea or redgram, are herbaceous members of the family Leguminoseae that grows widely throughout Africa, Asia and South and Central America. Cajanus spp. have been used in traditional medicine to treat stomach aches for women suspected of being pregnant, wounds and scalds, toothache, gonorrhoea, bad vision and heart diseases (Hedberg, H, et al., J Ethnopharmacol, 9 (2/3), 237-260 (1983).
In addition to its use by traditional healers, these plants may also be included in the normal diet as a food plant. Canjanus spp, for example, are consumed by people in India. To that end, studies have reported redgram and blackgram consumption""s effect on blood glucose levels and glucose tolerance. (Srinivasan, M., Lancet 1957, 317 (1957)).
Extracts of Cajanus cajan have been reported to show hyypoglycemic activity. Dhar reported a 50% ethanolic extract of Cajanus cajan as exhibiting hypoglycemic activity. Dhar, M. L., et al., Indian J. Exp. Biol., 6, 232 (1968).
While extracts of the genus Cajanus have been used medicinally, such use is not without potential drawbacks. First, in addition to containing one or more compounds having a xe2x80x9cdesiredxe2x80x9d biological activity, plant materials often contain a myriad of naturally-occurring organic compounds among which one or more can elicit a physiological or pharmacological response that contraindicate use for the desired activity. Secondly, when administered in the form of a plant extract, the actual dosage of the unknown active compound(s) is impossible to regulate, which can result in an ineffective amount, i.e, too low a concentration, or a toxic amount, too high a concentration, of active compound administered.
Thus, there remains a need for an isolated or a purified, hypoglycemically active compound, compositions comprising therapeutically effective amounts of such a compound and methods for their use.
Compounds Isolated from Cajanus SPP
Stilbenoids
The term stilbenoid refers to stilbenes, bibenzyls and phenyldihydroisocoumarins together with a number of nitrogen free phenathrenols, which are thought to be products of the same metabolic pathway that leads to stilbenes. See generally Gorham, J., Progress in Phytochemistry, Vol. 6, Reinhold, et al., eds, Pergamon press, New York, 1980, pp 203-252. Stilbenes (dihydrostilbenes) generally have the basic two stereoisomeric forms, a trans- and a cis-skeleton: 
Generally, naturally occurring stilbenes and bibenzyls are hydroxy and/or methoxy substituted at the 3,3xe2x80x2,4,4xe2x80x2,5, and 5xe2x80x2 positions. Some naturally occuring stilbenes and bibenzyls include pinosylvin (3,5-dihydroxy stilbene), piceatannol (3,3xe2x80x2,4,5xe2x80x2-tetrahydroxlystilbene), piceid (3,4xe2x80x2,5-trihydroxystilbene-3-O-xcex2-D-glucopyranoside) and resveratrol (3,4xe2x80x25-trihydroxystilbene). Mono- (3-hydroxy-5-methoxystilbene) and di-methyl (3,5-dimethoxystilbene) ethers of trans-pinosylvin and their respective dihydroderivatives have been reported isolated from the heartwood of Pinus armandi, P. morrisonicola, and P. parviflorai. Fang, J-M, et al. Phytochemistry 27(5): 1395-1397 (1988).
Stilbenoids may also be prenylated or homogeranylated at the ortho (C-2 or C-6) or para (C-4) positions. Longistylines A (3-hydroxy-5-methoxy-4-(3-methyl-2-butenyl)stilbene), B (3,5-dihydroxy-2,4-di(3-methyl-2-butenyl)stilbene), C (3-hydroxy-5-methoxy-2-(3-methyl-2-butenyl)stilbene, and D (3,5-dihydroxy-2,6-di(3-methyl-2-butenyl)stilbene) were isolated from the bark and root of Lonchocarpus longistylus. Monache, F. D., et al. (Lloydia 40(2), 201-208 (1977)). 4-isopentenylresveratrol (3,4xe2x80x2,5-trihydroxy-4-(3-methyl-2-butenyl)stilbene) was isolated from Arachis hypogea (Keen, N. T., et al., Phytochemistry 15, 1794 (1976)). A prenylated pinosylvin dimethyl ether (3,5-dimethoxy-4-(3-methyl-2-butenyl)stilbene) was isolated from Derris rariflora (Braz Filho, R., et al., Phytochemistry 14, 261 (1975a)) and D.floribunda (Braz Filho, R., et al., Phytochemistry 14, 1454 (1975b)). A prenylated resveratrol trimethyl ether (3,4xe2x80x2,5-trimethoxy-4-(3-methyl-2-butenyl)stilbene) was also reported isolated from D. floribunda (Braz Filho, R., et al., 1975b). Chlorophorin (4-homogeranyl-2,3xe2x80x2,4,5xe2x80x2-tetrahydoxysilbene) was isolated from Chlorophora excelsa (Grundon, M. F., et al., Nature (Lond.) 163, 154 (1949)). The occurrence in plants of isoprenice chains substituted stilbenes has also been reported by King and Grundo (J. Chem. Soc. 1950, 3547 (1950)); and Cooksey (Cooksey, C. J., et al., Phytochemistry 21(12), 2935 (1982)).
Prenylated bibenzyls have been isolated from Radula spp. Asakawa, Y, et al., reported the isolation of 3,5-dihydroxy-4-(3,7-dimethyl-2,6-octadienyl)-bibenzyl from R. variabilis (Phytochemistry 17, 2005 (1978a)) as well as the synthesis of mono and dimethyl ethers and corresponding tetrahydroderi-vatives. Asakawa reported the isolation from Radula complanata of bibenzyls prenylated or geranylated at 4 position. Asakawa, Y. et al., Phytochemistry 17, 2115 (1978b). Asakawa also reported the isolation of prenyl bibenzyls from Radula kojana. Asakawa, Y., et al., Phytochemistry 30(1), 219 (1991).
Four isoprenylated stilbene 2-carboxylic acid phytoalexins (3-hydroxy-5-methoxy-6-(3-methyl-2-butenyl)stilbene-2-carboxylic acid, 3-hydroxy-5-methoxy-4-(3-methyl-2-butenyl)stilbene-2-carboxylic acid, 3,5-dimethoxy-6-(3-methyl-2-butenyl)stilbene-2-carboxylic acid, and 3,5-dimethoxy-4-(3-methyl-2-butenyl)stilbene-2-carboxylic acid) were reported isolated from the leaves of Canjanus cajan challenged with Botrytis cinierea (Cooksey, C J, et al., Phytochemistry 21(12):2935-2938 (1982).
Various biological activities have been reported of the stilbenoids. For example, stilbenoids have been reported to show antioxidant activities [resveratrol] (A. Fauconneau, B., et al., Life Sci. 61(21):2103 (1997)); antifungal activity [3,3xe2x80x2,4,5xe2x80x2-tetrahydroxystilbene](Inamori, Y., et al., Chem. Phar. Bull. 33(7):2904-09 (1985)); antiplatelet aggregation activity [resveratrol] (Chung, M-I, et al., Planta Med. 1992 58:274-275; and Kimura, Y., et al., Biochim.Biophys. Acta 1995 175, 275-278); coronary vasodilator activity (Inamori, Y., et al., Chem. Pharm. Bull. 35, 887-89 (1987); anti-leukemia activity (Mannila, E., Phytochemistry, 1003, 33, 813-816) and protein-tyrosine kinase inhibitory activity (Orsini, F., et al., J. Nat. Prods. 60, 1082-1087 (1997)).
Pterostilbene (3,4xe2x80x2,5-trimethoxystilbene) isolated from Pterocarpus marsupium reportedly significantly decreased the plasma glucose level and body weights of of STZ-induced diabetic rats. Manickam, M., et al., J. Nat. Prods. 60, 609-610 (1996). Both the aqueous and alcoholic extracts of the heartwood of Pterocarpus marsupium were reported to produce a reduction in blood sugar level. Shah, D. S., Ind. J. Med. Res. 55(2), 166-168 (1967).
International patent application WO00/69430 by Nag et al. and published on Nov. 23, 2000 describes diphenylethylene compounds having the formula: 
wherein,
R is hydrogen or xe2x80x94CO2Z, Z is hydrogen or a cation;
R1, R2, and R3 are each independently H, xe2x80x94OH, or OR4, wherein R4 is linear or branched alkyl of 1-12 carbon atoms; with the proviso that when R is hydrogen and R2xe2x95x90R30Me, then R2 is not OH.
These compounds are allegedly useful for the treatment of diabetes.
Citation or identification of any reference in the Background of this application shall not be construed as an admission that such reference is available as prior art to the present invention.
The present invention provides pharmaceutical compositions useful for treating hyperglycemia or reducing blood glucose levels comprising a pharmaceutically acceptable carrier and an effective amount of an isolated compound having the formula (I): 
wherein,
A is selected from the group consisting of a single bond and a double bond in trans conformation, as noted by - - - -;
R1 is selected from the group consisting of H, OH, C1-6alkoxy, COOH, and COOC1-6alkyl;
R2 is selected from the group consisting of H, OH, and C1-10alkoxy;
R3 is selected from the group consisting of H, C1-10alkyl, C2-10-alkenyl, C2-10alkynyl, and C1-8cycloalkyl;
R4 is selected from the group consisting of H, OH, and C1-10alkoxy;
R5 are selected from the group consisting of H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, and C1-8cycloalkyl;
R6 is selected from the group consisting of H, OH, C1-6alkoxy, COOH, and COOC1-6alkyl;
R7 is selected from the group consisting of H, OH, C1-6alkoxy, COOH, and COOC1-6alkyl; and
wherein at least one of R3 and R5 is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl; and C1-8cycloalkyl;
or a pharmaceutically acceptable salt thereof.
The present invention also provides methods for treating hyperglycemia or reducing blood glucose levels to a mammal comprising administering to said mammal a hypoglycemically effective amount of an isolated or pure compound of formula (I). In particular embodiments, the invention provides methods of treatment for type I diabetes, type II diabetes, hyperthermia, trauma, sepsis, burns, severe head injury, cerebral-thrombosis, encephalitis, heat stroke, congenital metabolic glycogen storage diseases, and hyperglycemia that occurs as a adverse advent of anesthesia.